Mitofusin-2 in nucleus accumbens D2-MSNs regulates social dominance and neuronal function

Abstract

SummaryThe nucleus accumbens (NAc) is a brain hub regulating motivated behaviors, including social competitiveness. Mitochondrial function in the NAc is critically implicated in the association between anxiety and social competitiveness, and the mitochondrial fusion protein mitofusin 2 (Mfn2) in NAc neurons has been shown to regulate anxiety-related behaviors. However, it remains unexplored whether accumbal Mfn2 levels also affect social behavior and whether Mfn2 actions in the emotional and social domain are driven by distinct cell types. Here, we found that subordinate-prone highly anxious rats show reduced accumbal Mfn2 levels and that Mfn2 overexpression promotes dominant behavior. In mice, selective Mfn2 downregulation in NAc dopamine D2 receptor-expressing medium spiny neurons (D2-MSNs) induced social subordination, accompanied by reduced mitochondrial function and decreased neuronal excitability. Instead, D1-MSN-targeted Mfn2 downregulation affected competitive ability only transiently mainly by increases in anxiety-like behaviors. Our results assign dissociable cell-type specific roles to Mfn2 in the NAc in modulating social dominance and anxiety.